title: L-Aminoacyl-triazine derivatives are isoform-selective PI3Kβ inhibitors that target non-conserved Asp862 of PI3Kβ
abstract: A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform selective inhibitors of PI3Kβ. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3Kβ while their D-congeners favoured PI3Kδ. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862 was identified as a critical participant in binding to the PI3Kβ-selective inhibitors distinguishing this class from other reported PI3Kβ-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052 Australia.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Pinson
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zheng
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Miller
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
keywords: PI3 kinase; ZSTK474; cancer; p110β